| Epilepsy is one of the most commonly seen neurological disorders, just secondary to cerebral vascular diseases in incidence and prevalence. According to the most recently statistics by WHO, the prevalence of epilepsy is 5‰～11.2‰ with no apparent difference regarding both nationality and religion. Epidemiological survey shows the prevalence and incidence of epilepsy in China is 5‰ and 35/10, 000 per year. About 70% of all patients with epilepsy can be treated with satisfactory results with antiepileptic drugs , the remaining 30% do not respond to antiepileptic drugs well, epilepsies in these patients are called intractable epilepsy or drug resistant epilepsy or medical refractory epilepsy. 50% of patients with epilepsy that does not respond to medical treatment well can be treated surgically with good results. For a long time, temporal lobe epilepsy has predominates the surgical series of epilepsy. Temporal lobe epilepsy is generally classified into two subtypes according to seizure origin: lateral and mesial. Different pathologies have been associated with temporal lobe epilepsy. Yet, the mesial temporal lobe epilepsy associated with hippocampal sclerosis is the most important epileptic syndrome that is surgically remediable. Thus, mesial temporal lobe epilepsy associated with hippocampal sclerosis has been a research topic of interest in epileptological field. Over the past half century, epileptologists have devoted much effort into researches regarding the relationship between temporal lobe epilepsy and hippocampal sclerosis, the pathogenesis of hippocampal sclerosis, the molecular biochemical changes , mechanism underlying drug-resistance , surgical treatment and so on. But all these problems are still awaiting further study so as to be elucidated.This clinically based research includes three aspects: (1) to compare the advantage and disadvantage of the presently being used surgical procedures for mesial temporal lobe epilepsy associated with hippocampal sclerosis; (2) to observe the neuronal apoptotic evidence in the resected sclerotic hippocampal specimens from patients with mesial temporal lobe epilepsy associated with hippocampal sclerosis; (3) to observe the translational expressions of drug-resistance related genes in the resected sclerotic hippocampal specimens from patients with mesial temporal lobe epilepsy associated with hippocampal sclerosis. These observations were : (1) to provide objective evidence for the selection of surgical modalities in surgically treated patients with mesial temporal lobe epilepsy associated with hippocampal sclerosis in clinical settings; (2) to explore the mechanism underlying neuronal loss in hippocampal sclerosis, and to attempt to confirm that hippocampal sclerosis is a pathological entity with mesial temporal lobe epilepsy as the main clinical manifestation; (3) to explore the mechanism underlying drug-resistance in intractable epilepsy.The first part of this study was on the comparison of advantage and disadvantage of the presently being used surgical procedures for mesial temporal lobe epilepsy associated with hippocampal sclerosis. Backgroud and purpose: Temporal lobe epilepsy is the most frequent partial epileptic syndrome of all partial epileptic syndromes. Temporal lobe epilepsy includes two subtypes according to seizure origin: mesial and lateral , with the mesial much more frequent than the lateral. Hippocampal sclerosis is the main pathological substrate of mesial temporal lobe epilepsy. The majority of patients with mesial temporal lobe epilepsy associated with hippocampal sclerosis are candidates for surgical treatment. There are several surgical modes for this special epileptic syndrome, but rare comparative studies have been performed regarding them around the world. In this investigation, a comparative study was carried out to compare the effectiveness with respect to seizure control and risks in the following three surgical modalities-anterior medial temporal resection, transsylvian fissure selective amygdalohippocampectomy and transcortical transventricular selective amygdalohippocampectomy, in order to explore the advantage and disadvantage inherent in the surgical modalities, and thus , to provide useful guideline for clinical practice. Methods Based on seizure history, seizure semiolgy, findings with long-term video-EEG monitoring and high resonance MRI scanning, 73 patients with mesial temporal lobe epilepsy associated with unilateral hippocampal sclerosis refractory to medical treatment were consecutively selected and operated on for seizures. 20, 23 and 30 patients underwent transcortical transventricular selective amygdalohippocampectomy, transsylvian fissure selective amygdalohippocampectomy and anterior medial temporal resection respectively. All the surgical procedures were carried out with microsurgical techniques. All patients were followed up at least for more than one year. Engel' s outcome scale was employed for the evaluation of postoperative outcomes with respect to seizures. All postoperative complications and influence of surgery on memory were analyzed according to prospectively documented data. Results Routine pathological study showed typical changes of hippocampal sclerosis. Regarding outcomes with respect to seizure control, the three surgical methods were not statistically different with high frequency of seizure freedom in this special epileptic syndrome. There was not surgical mortality. No mortality occurred in all patients during the follow-up period. The main surgical complications included diplopia, intracranial infection. All these complications were transient and cured, and had no significant difference in occurrence among the three groups. Conclusions In strictly selected patients with mesial temporal lobe epilepsy associated with hippocampal sclerosis, selective amygdalohippocampectomy and anterior medial temporal resection are comparable on outcomes with respect to seizures. All the three surgical procedures are safe, and thus, at least initially, these three procedures should be choosed based on surgical experiences of operators.The second part of this study is on the observation of neuronal apoptosis in the resected sclerotic hippocampus of patients with mesial temporal lobe epilepsy. Background and purpose It is well known that the pathological changes of hippocampal sclerosis are characterized by selective neuronal loss and gliosis. Yet, the pathogenesis underlying hippocampal sclerosis is not well known. In this study, the surgically resected hippocampal specimens with typical hippocampal sclerosis changes as confirmed by routine pathological study from patients with mesial temporal lobe epilepsy were investigated with electron microscope and immunohistological staining in order to explore whether or not apoptosis is associated with the pathogenesis of hippocampal sclerosis. Methods 24 hippocmapal specimens were obtained surgically during the surgical treatment of patients with mesial temporal lobe epilepsy associated with unilateral hippocampal sclerosis diagnosed with MRI. Apoptosis was detected with light microscope, electron microscope and TUNEL. Immunohistological staining was performed with anti-bcl-2, anti-p53, anti-bax, anti-fas and anti-caspase-3 to observe the expression of these apoptosis-related genes at translational level. 6 hippocampal specimens from 3 cadavers died from non-neurological diseases were as controls. Results No apoptotic neural cells were found with light microscope, electron microscope and TUNEL staining. In the sclerotic hippocampi from 3 patients, neurons with early apoptotic changes were found with electron microscope. Bcl-2 was not expressed in the brain tissue from controls but expressed remarkably in the specimen from epileptic patients( (t=2.97, P<0.01) . P53 was not expressed in the brain tissue from controls but expressed remarkably in the specimen from epileptic patients (t=2.31, P<0.05) ;Bax was expressed mildly in both the controls and epileptic patients with no significant difference (t=0.41, P>0.05) ;fas . P53 was not expressed in the brain tissue from controls but expressed remarkably in the specimen from epileptic patients (t=4.58, P<0.001) ; caspase-3 was mildly expressed in the controls and remarkably expressed in the epileptic patiens (t=3.03, P <0.01) .Conclusions Apoptotic process may involved in the genesis of hippocampal sclerosis. p53,fas and caspase-3 may play important roles in the development of apopotosis which may related with the occurrence of sclerotic changes of hippocampus in patients with mesial temporal lobe epilepsy. The expression of bcl-2, a suppressor gene for apoptosis, in hippocampus of patients with mesial temporal lobe epilepsy, may be a compensative response to the ocuurence of apoptosis, thus, proving that apoptosis ocurr in hippocmapal sclerosis from another aspect.The third part of this study was devoted into the observation of expression of drug-resistace related genes in the sclerotic hippocampi from patients with mesial temporal lobe epilepsy. Background and purpose Drug-resistance is a very common phenomenon with a large variety of medications. A lot of researches have been devoted into the exploration of mechanisms underlying chemotherapy for cancer and the results shows that drug-resistance in patients with cancer unresponsive to chemotherapy is related with increased expression of multidrug related genes. It is assumed that the mechanism underlying the refractoriness of epilepsy to antiepileptic drugs may also related with increased expression of multidrug related genes or others. Mesial temporal lobe epilepsy associated with hippocampal sclerosis is surgically remediable and thus the specimen of sclerotic hippocampus is easy to obtain in clinical settings. So it is a good human model for the investigation of mechanism underlying drug-resistance in epilepsy. This research was to observe the protein expressions of drug-resistance related genes in order to insight into mechanism with drug-resistance in epilepsy. Methods 16 patients with mesial temporal lobe epilepsy associated with hippocampal sclerosis were selected according to seizure history, seizure semiology, MRI finding and EEG recording. All these patients had unilateral hippocampal sclerosis diagnosed with MRI and had a long history of using antiepileptic drug treatment under the direction of epileptologists. The seizures in these patients were refractory to multiple antiepileptic drugs before surgery. All these patients underwent anterior medial temporal resection or selective amygdalohippocampectomy. The diagnosis of hippocampal sclerosis was confirmed with pathological study in all patients. In this study, the expressions of glycoprotein p 170(p-gp170),glutathione-S-transferase π (GST-π),topoisomerase II(TOP II),Thymidylate Synthase(TS) and 06-methylguanine DNA methyltransferase (MGMT ) in the sclerotic hippocampi from these patients were measured using immunohistochemical staining with 6 hippocampi from 3 individuals died from non neurological diseases as controls. Results The expression of p-gp170 was not detectable in hippocampi from controls but remarkable in neurons, vascular endothelial cells and glial cells in the sclerotic hippocampi from patients with mesial temporal lobe epilepsy, especially more remarkable in vascular endothelial cells and glial cells. Similarly, the expression of GST π was not detectable in hippocampi from controls but remarkable in neurons, vascular endothelial cells and glial cells in the sclerotic hippocampi from patients with mesial temporal lobe epilepsy, especially more remarkable in vascular endothelial cells and glial cells. The expressions of TOPII,TH and MGMG were not expressed remarkably both in hippocampi from controls and in those from patients. Conclusions p-gp170 is the translational product of multidrug gene 1 (MDR1 ) , which is transmembranous ATP dependent molecular pump related functionally with cellular secretion and exocytosis. GST- π is an important enymatic catalyst involving the process of converting lipophilic substances into hydrophilic ones and that of discharging these substances out of the body. The results of this study indicate that long-term usage of antiepileptic drugs can promote the expressions of p-gp170 and GST-π,which in turn enhance the excretion and metabolism of the drugs used, leading to the phenomenon of drug-resistance. TOPII,TH and MGMG could possibly be unrelated with the drug-resistance phenomenon in chronic epilepsy.
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